Self & Other · Autoimmune Disease: Friendly Fire
The Family of Diseases
The autoimmune attack on the beta cells is slow. It can take years. By the time symptoms appear — the thirst, the weight loss, the eventual ketoacidosis — most of the beta cells are usually already gone. There is some emerging evidence that the process may sometimes be detectable earlier, in the form of certain antibodies that turn up in the blood years before symptoms, but for most people the diagnosis is the first they know of it. By the time Maya was in the ER, more than ninety percent of her beta cells were probably already dead. The remaining ones could not produce enough insulin to handle a meal.
Other autoimmune diseases work along similar lines, but with different targets. In multiple sclerosis, T cells attack the myelin sheaths that insulate nerves in the brain and spinal cord. In rheumatoid arthritis, an immune response targets proteins in the joints, particularly in the synovial tissue that lines them. In Hashimoto’s thyroiditis, the thyroid is the target. In celiac disease, T cells respond to a protein from wheat in a way that, through molecular mimicry, also damages the lining of the small intestine. In lupus, multiple tissues are involved at once — skin, joints, kidneys, sometimes the brain — because the antibodies and T cells produced are reactive against widespread cellular components rather than against any single organ.
The list, by 2025, runs to about eighty conditions. Together, they affect somewhere between five and ten percent of people — the exact number depends on how you count and which country you are in. They are, as a group, one of the most important categories of disease in modern medicine. Some of them, like Type 1 diabetes, are diseases people are born with the predisposition for and develop early. Others, like rheumatoid arthritis or lupus, more commonly appear in young adulthood. A few, like Hashimoto’s, often appear in middle age. Almost all of them are chronic. Almost all of them are managed, not cured.
The Family of Diseases
It is worth saying, briefly, what kinds of autoimmune disease there are, because the public conversation often treats them as one thing and they are not.
The most useful first division is between organ-specific and systemic autoimmune diseases.
Organ-specific diseases involve an immune response against a single tissue. Type 1 diabetes is the classic example: the attack is on the beta cells of the pancreas, and only on the beta cells. The rest of the pancreas, and the rest of the body, are not under attack. Hashimoto’s thyroiditis attacks the thyroid. Graves’ disease, oddly, also attacks the thyroid but does the opposite — it produces antibodies that overstimulate the gland rather than destroying it. Multiple sclerosis attacks the myelin in the central nervous system. Vitiligo attacks the pigment-producing cells in the skin. Pernicious anemia attacks the cells in the stomach that absorb vitamin B12. The list is long, and the diseases vary from life-threatening to mostly cosmetic, but they share the feature that the immune response is focused on one place.
Systemic diseases are different. In lupus, in rheumatoid arthritis, in Sjogren’s syndrome, in mixed connective tissue disease, the immune response targets components that exist in many tissues at once. The result is a disease that can show up almost anywhere. A person with lupus may have rashes, joint pain, kidney problems, and fatigue, all at the same time, all driven by the same underlying loss of tolerance. The challenge in systemic disease is partly that no single organ tells the story; the disease is everywhere and nowhere.
A third category, the inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), sit somewhere in between. They are organ-focused — they affect the gut — but the gut is enormous, and the diseases involve a complex interaction between the immune system, the gut microbiome, and the gut lining we met in Chapter 5. The boundary between “autoimmune” and “immune-mediated inflammatory” gets blurry here, and the field has not entirely settled on a single label. For practical purposes, what matters is that the same kinds of immune mechanisms are involved, and many of the same treatments work.
A fourth category, sometimes overlapping with the others, includes diseases like psoriasis and ankylosing spondylitis, where the immune system targets specific tissues but the dominant mechanism is not a clean attack on one protein but a chronic inflammatory state driven by a particular signaling pathway. We will see, in a moment, why this distinction matters when we talk about treatment.
Why Women, Mostly
Roughly eighty percent of people with autoimmune disease are women.
This is one of the more striking facts in immunology, and it has been known for decades, and we still do not fully understand it.
Several things are probably going on at once. Some autoimmune diseases respond to female sex hormones — estrogen, in particular, can amplify certain kinds of immune response, and many autoimmune conditions worsen during phases of life when estrogen is high and improve during phases when it is low. Pregnancy, with its enormous hormonal shifts, can both trigger autoimmune disease and, occasionally, put it temporarily into remission. After menopause, some autoimmune diseases get better and others get worse.
But hormones cannot be the whole story, partly because some autoimmune diseases (like ankylosing spondylitis) are more common in men, and partly because the female bias appears even before puberty in some conditions.
A more recent and active area of research focuses on the X chromosome. Women have two X chromosomes; men have one. Most of the genes on one of the two X chromosomes in any given female cell are silenced, in a process called X-inactivation, so that women don’t end up making double the amount of every X-linked protein. But X-inactivation is not perfect. Certain genes routinely escape it, and many of those escaping genes are involved in the immune system. There are interesting recent findings suggesting that this incomplete inactivation may produce small but consistent differences in immune regulation between women and men, and that those differences may tilt the odds toward autoimmunity.